Abstract Leukodystrophies are rare inherited diseases that affect the white matter of the brain due to the loss or absence of myelin, the lipid membrane that insulates axons in the nervous systems. Despite disparate molecular etiologies, similar functional impairments are common across these disorders and generally appear to associate with disease progression. Nevertheless, clinical outcome assessments (COA) are critically lacking, with very few validated tools available for use in clinical trials. This proposal will advance the clinical trial readiness of leukodystrophy by creating a trial-ready tool-box and multi-center data integration systems. Further, the project will catalyze ongoing efforts of the leukodystrophy community by bringing together more than a dozen patient advocacy groups, industry stakeholders, and two pre- existing leukodystrophy consortia. Using this framework, we will assess the validity of existing clinical outcome assessment tools in leukodystrophy (Aim 1). We will also deploy patient reported outcome measures to better understanding of the progression of leukodystrophies (Aim 2). Finally, we will deploy integrative technologies leveraging the electronic medical record (EMR) to identify and categorize natural history data contributing to a data-driven phenotype of leukodystrophies (Aim 3). Methodologies will undergo face validation, inter-rater reliability, reproducibility, longitudinal stability, internal validation and construct validity under the careful oversight of our data integration core and advocacy partners. Our anticipated impact is to define the best tools to understand natural history in individuals with leukodystrophy. This longitudinal study will provide a body of data and management approaches that will inform and empower our companion projects and future goals of the scientific, advocacy and commercial stakeholders in the leukodystrophies.